PROJECT SUMMARY Mounting evidence suggests that it is feasible to alleviate chronic disorders of aging as a group by targeting the biology of aging. Because interventions that enhance healthspan (i.e., the healthy period of life free of chronic disease) and extend lifespan in mammals now exist, we hypothesize that clinical interventions targeting fundamental mechanisms of aging will delay or alleviate age-related disabilities and diseases as a group, rather than the current paradigm of treating each separately. This may be feasible by targeting one such fundamental aging mechanism ? cellular senescence. Here we focus on osteoporosis, a common late-life disease that often co-exists with other chronic diseases and leads to ~2 million fractures and ~$17 billion in healthcare costs annually, by examining the effects of targeting senescent cells, using ?senolytics? ? i.e., drugs that selectively induce senescent cell apoptosis, on skeletal health in older humans. Our compelling preliminary data implicate cellular senescence at the nexus of skeletal aging. They also provide evidence for selectively eliminating senescent cells as an innovative and conceptually novel approach to address the enormous problem of age-related bone loss that is now ready for human testing. Therefore, given that senescent cells are present at the time and location of age-related bone loss in humans as in mice, we hypothesize that clinical interventions targeting senescent cells will delay or alleviate age-related bone loss in older humans. Thus, we will perform a crucial, ?proof-of-concept? 20-week, placebo-controlled, randomized controlled trial to rigorously test whether targeting senescent cells with senolytic therapy improves skeletal health in older humans. To test this hypothesis, we propose the following Specific Aim: In a cohort of 120 older postmenopausal women, aged 70-90 yrs, with a high senescent cell burden (as these individuals are most likely to benefit from pharmacological interventions that eliminate senescent cells ? i.e., senolytics), we will test the efficacy of intermittent senolytic therapy as compared to placebo therapy on improving bone turnover markers and skeletal parameters over the course of 20 weeks (Aim 1a). We will further assess the impact of senolytics as compared to placebo on reducing systemic surrogate markers of senescent cell abundance and circulating senescence-associated secretory phenotype (SASP) factors (Aim 1b). Translating drugs targeting basic aging processes, such as cellular senescence, into interventions to alleviate chronic diseases and age-related disabilities is novel from the perspective of basic/clinical research, clinical care, and healthcare policy. Our goal is to test the efficacy of interventions that target senescent cells to alleviate skeletal aging. Based on strong preclinical data demonstrating efficacy in mice, our group is now primed to test senolytics for alleviating age-related bone loss in human trials. If our hypothesis is correct, the impact on clinical practice and healthcare would be substantial and potentially of paramount importance.